Serotonin2B receptor blockade in the rat dorsal raphe nucleus suppresses cocaine-induced hyperlocomotion through an opposite control of mesocortical and mesoaccumbens dopamine pathways
Serotonin2B receptor blockade in the rat dorsal raphe nucleus suppresses cocaine-induced hyperlocomotion through an opposite control of mesocortical and mesoaccumbens dopamine pathways
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DOI：
10.1016/j.neuropharm.2020.108309
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发表时间：
2020-12-01
影响因子：
4.7
通讯作者：
Spampinato, Umberto
中科院分区：
文献类型：
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作者：
Cathala, Adeline;Devroye, Celine;Spampinato, Umberto
5-羟色胺(2B)受体(5-HT2BR)拮抗剂不依赖于伏隔多巴胺(DA)释放的变化而抑制可卡因诱导的多动。鉴于伏核DA活动与运动之间的密切关系，以及内侧前额叶(MPFC)DA对皮质下DA神经传递和DA依赖行为的抑制作用，有人认为5-HT2BR拮抗剂对可卡因诱导的多动抑制作用可能是激活mPFC DA流出，从而抑制伏核DA神经传递。在这里，我们通过两种选择性的5-HT2BR拮抗剂RS 127445和LY 266097，结合神经化学、行为和细胞方法在雄性大鼠身上验证了这一假说。注射RS 127445(0.16 mg/kg)或LY 266097(0.63 mg/kg)可增强可卡因(10 mg/kg)诱导的mPFC DA外流。在6-羟基多巴胺损毁的大鼠中，RS-127445对可卡因诱导的大鼠多动不再有抑制作用。此外，RS 127445阻断了可卡因引起的伏隔糖原合成酶K313磷酸化的改变，该磷酸化是DA神经传递的突触后细胞标志。最后，与5-羟色胺(2B)受体在中缝背核GABA能中间神经元上的位置一致，GABA受体拮抗剂荷包牡丹碱(100mU M)在中缝背核(DRN)内灌流GABA能中间神经元，可阻止全身或局部(1mU M，DRN内)RS 127445对可卡因诱导的mPFC DA外流的影响。同样，背根神经节内注射荷包牡丹碱(0.1mU g/0.2mU L)可阻断全身注射RS 127445对可卡因诱导的大鼠多动症和GSK313磷酸化的影响。这些结果表明，DRN5-HT2BR阻断可通过增强可卡因诱导的大鼠中脑前叶DA外流，进而抑制伏核DA神经传递而抑制可卡因诱导的大鼠多动。
Serotonin(2B) receptor (5-HT2BR) antagonists inhibit cocaine-induced hyperlocomotion independently of changes of accumbal dopamine (DA) release. Given the tight relationship between accumbal DA activity and locomotion, and the inhibitory role of medial prefrontal cortex (mPFC) DA on subcortical DA neurotransmission and DA-dependent behaviors, it has been suggested that the suppressive effect of 5-HT2BR antagonists on cocaine -induced hyperlocomotion may result from an activation of mPFC DA outflow which would subsequently inhibit accumbal DA neurotransmission. Here, we tested this hypothesis by means of the two selective 5-HT2BR antagonists, RS 127445 and LY 266097, using a combination of neurochemical, behavioral and cellular approaches in male rats.The intraperitoneal (i.p.) administration of RS 127445 (0.16 mg/kg) or LY 266097 (0.63 mg/kg) potentiated cocaine (10 mg/kg, i.p.)-induced mPFC DA outflow. The suppressant effect of RS 127445 on cocaine-induced hyperlocomotion was no longer observed in rats with local 6-OHDA lesions in the mPFC. Also, RS 127445 blocked cocaine-induced changes of accumbal glycogen synthase kinase (GSK) 313 phosphorylation, a post -synaptic cellular marker of DA neurotransmission. Finally, in keeping with the location of 5-HT(2B)Rs on GABAergic interneurons in the dorsal raphe nucleus (DRN), the intra-DRN perfusion of the GABAAR antagonist bicuculline (100 mu M) prevented the effect of the systemic or local (1 mu M, intra-DRN) administration of RS 127445 on cocaine-induced mPFC DA outflow. Likewise, intra-DRN bicuculline injection (0.1 mu g/0.2 mu l) prevented the effect of the systemic RS 127445 administration on cocaine-induced hyperlocomotion and GSK313 phosphorylation.These results show that DRN 5-HT2BR blockade suppresses cocaine-induced hyperlocomotion by potentiation of cocaine-induced DA outflow in the mPFC and the subsequent inhibition of accumbal DA neurotransmission.